Background: The endoplasmic reticulum (ER) stress pathway may play a role in the pathogenesis multiple sclerosis (MS), and while ER stress-associated molecules have been demonstrated in white matter (WM) lesions, these have not been analysed in grey matter (GM) demyelination.

Objective: The objective was to characterise the type and frequency of GM lesions and establish expression profiles of ER stress- and hypoxia (Lack of oxygen)-associated markers.

Results: Of the GM lesions analysed, 24% were type 1 (continuous between GM and WM), 22% were type 2 (entirely within GM) and the majority (54%) were type 3 (extending from pia mater). Comparison of GM lesions, MS normal-appearing grey matter (NAGM) and non-MS control tissue showed that NAGM, type 1 and type 3 lesions all had significantly increased levels of CHOP compared to controls. According to morphological and dual-labelling criteria, the majority of CHOP-positive cells were microglia. Approximately 50% of GM lesions contained D110-positive cells.

Conclusion: These data suggest that ER stress plays an important role in GM lesion development and may be critical in activation of microglia in pre-lesional NAGM. The high number of lesions containing D110-positive cells suggests a role for hypoxic-like insult in GM lesion development.

Inside of a cell

There are markers associated with the misfolding of protein strucutures in the protein factories (endoplasmic reticulum) of the cells in grey matter lesions in MSers. The production of CHOP favours the production of cell death, because it causes down regulation of mitochondrial protein Bcl-2, that controls and protects cells from death. This therefore favouring a pro-cell death drive at the mitochondria (the energy powerhouse of the cell) by proteins that cause mitochondrial and cell damage. These authors suggest that there may be damage caused by hypoxia. This is lack of oxygen, which occurrs in stroke where it is associated with blocked vessels. However, these molecules are associated with patholgy. This study tells us that there are damaging processes occuring in MS lesions.

Anti-myelin immunity is commonly thought to drive multiple sclerosis, yet the initial trigger of this autoreactivity remains elusive. One of the proposed factors for initiating this disease is the primary death of oligodendrocytes. To specifically test such oligodendrocyte death as a trigger for anti-CNS immunity, we inducibly killed oligodendrocytes in an in vivo mouse model. Strong microglia-macrophage activation followed oligodendrocyte death, and myelin components in draining lymph nodes made CNS antigens available to lymphocytes (white blood cells) . However, even conditions favoring autoimmunity—bystander activation, removal of regulatory T cells, presence of myelin-reactive T cells and application of demyelinating antibodies—did not result in the development of CNS inflammation after oligodendrocyte death. In addition, this lack of reactivity was not mediated by enhanced myelin-specific tolerance. Thus, in contrast with previously reported impairments of oligodendrocyte physiology, diffuse oligodendrocyte death alone or in conjunction with immune activation does not trigger anti-CNS immunity.When I first read the comment in the blogger comments that the "Neurodegenerative hypothesis for the causes of MS is obsolete and researchers should be looking at the immune system and not the CNS" I thought that they were taking about the neurodegenerative hypothesis in progressive MS. To think that this is caused by influences outside the CNS and the immune system, is just pants, because I do not think the (lymphocyte) immune system is the problem there.However the neurodegenerative hypothesis is a hypothesis (idea) not about nerve damage (neurodegenerative) but an idea about oligodendrocyte damage, so gliadegenerative. This study is looking into the idea that oligodendrocyte damage is a trigger for immune attack in the first place.As you know when you look at MS there is evidence of oligodendrocyte damage often in the absence of lymphocytes (a type of white blood cell), which some people think cause the problems with multiple sclerosis. This oligodendrocyte damage is thought by some, to trigger an immune attack of more oligodendrocytes. What causes the oligodendrocyte damage is unproven some may say viral attack others will say an inappropriate immune attack. So what did this study do?

They made a genetically-engineered mouse where the myelin-forming cells called oligodendrocytes make a target for the diptheria toxin which in normal mice would do nothing, but in these genetically engineered mice it causes the destruction of the oligodendrocytes so you have oligodendrocyte death so what happened next? Did the mice develop multiple sclerosis-like disease, even when in an inflammation-prone state? Well the answer is NO....so the conclusion that death of oligodendrocytes is not enough to cause immune attack of further oligodendrocytes. So we have to think about a different way that multiple sclerosis can be triggered. The solution is we should look outside the brain to work how MS starts. Hmmm not so sure.

Now the first thing that some of you will say is that, this is animal work and animals do not get MS and so blah, blah, blah.....so once you decide to read-on, you have moved away from this counter-productive response.

Then there are the others that will say that this study shows that MS is not an autoimmune disease caused by and causing oligodedendrocyte destruction. Indeed there are many like Prof G that think that this work will further support their view that the cause of MS is the work of some thing like a virus and this autoimmunity stuff is all guff. This is the message that this paper is attempting to get across........ they may be right, so bring on the Charcot Project. They killed oliogdendrocytes and caused demyelination but this did not lead to lymphocyte activation and did not cause an MS-like disease. They looked but could not find evidence that damage to oligodendrocytes can trigger MS attacks.

However, the problem of getting experiments that essentially do not work as planned could mean that rather than the idea being wrong, the wrong experimental design was used. So the autoimmuners still have a way to keep their beliefs and accomodate this new study.

So what did the study show? Well if you kill oligodendrocytes you get demyelination and animals (and presumably humans) develop neurological sysmptoms as a consequence of demyelination. Indeed in this study the mice actually died and this is perhaps a problem as this down-hill spiral (of about 2-3 weeks) may have been too quick for a proper destructive autoimmune response to develop. This takes time in animals and humans. They did try and reduced the amount of toxin to limit the amount of nerve damage and did this over months and still no MS-like disease. The researchers were looking mainly in the brain for the autoimmune response, when the autoimmune response may accumulate first in the spinal cord of mice as we learned previously (can you remember the gate in the lumbar spinal cord?)

Now next point they show that if you loose myelination, nerves are vulnerable to nerve damage. Indeed in this study the pictures tended to suggest that nerve loss may be dominant effect, as they really did not present very good evidence of long-standing demyelinated nerves, which we think occurs in MS.

They showed that they could not find evidence that the damage created by loss of oligodendrocytes in the brain led to lymphocyte stimulation in the lymph glands. However, the white blood cells they used to try and cause the MS-like disease, do not do their supposed job in some peoples hands. There are a few more experiments that could have been done that would clarify this, but we can say that for any piece of work.

Is this result surprising? Well perhaps not because there have been studies, in other similar genetically-engineered mice that show dysmyelination and demyelination and the development of autoimmunity was not yet reported. The strain of mouse they used has low susceptibility to MS-like disease, so maybe they did not model the genetic predispositions well enough as we know that many different factors come into play when MS is triggered.

However maybe the autoimmune hypothesis of MS is wrong and this is further evidence to support that view. Alternatively it may be that the anti-myelin autoimmune response is wrong and that the target in oligodendrocytes is something else. Time will tell. However if autoimmunity is a problem in MS, it is more likely that it is first stimulated in the lymph glands and then the damaging cells enter the brain. This is because the lymph glands are structurally specialised for this operation, the brain is not.

If indeed you can induce robust demyelination, without losing too many nerves, and killing the mice, These animals could be of real use in working how to promote remyelination. In this paper they report some evidence for remyelination so maybe just maybe.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

Diagnostic criteria for multiple sclerosis (MS) include clinical and paraclinical laboratory assessments emphasizing the need to demonstrate dissemination of lesions in space (DIS) and time (DIT) and to exclude alternative diagnoses. Although the diagnosis can be made on clinical grounds alone, magnetic resonance imaging (MRI) of the central nervous system (CNS) can support, supplement, or even replace some clinical criteria, as most recently emphasized by the so-called McDonald Criteria of the International Panel on Diagnosis of MS. The McDonald Criteria have resulted in earlier diagnosis of MS with a high degree of both specificity and sensitivity, allowing for better counseling of patients and earlier treatment.

Since the revision of the McDonald Criteria in 2005, new data and consensus have pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult populations from which the Criteria were derived. In May 2010 in Dublin, Ireland, the International Panel on Diagnosis of MS (the Panel) met for a third time to examine requirements for demonstrating DIS and DIT and to focus on application of the McDonald Criteria in pediatric, Asian, and Latin American populations.

This article can now be downloaded and viewed for free, to check out diagnosis of MS.

OBJECTIVE: To demonstrate the potential of ultrahigh-field 3-dimensional T1 weighted imaging using magnetization-prepared rapid acquisition and multiple gradient-echoes (MPRAGE) to detect and characterize white and gray matter pathology in MS.

METHODS: Twenty patients with relapsing-remitting MS and 14 healthy controls underwent 7-Telsa brain MRI, using a 24-channel receive head coil, and a subgroup of 18 patients with relapsing-remitting MS also underwent 1.5-T brain MRI. The imaging protocol included 2-dimensional T2-weighted fast low-angle shot (FLASH) and turbo inversion recovery magnitude (TIRM) sequences. For 3-dimensional T1-weighted imaging, the MPRAGE sequence was used. Each sequence was initially examined independently in separate analyses by an investigator blinded to all other data. In a second study, all detected lesions were retrospectively analyzed in a side-by-side comparison of all sequences.

RESULTS: By use of 7-Telsa, T2-weighted FLASH imaging, 604 cerebral (brain) lesions were detected in the patients with relapsing-remitting MS (mean, 30.2 lesions per patient [range, 2-107 lesions per patient]), but none were detected in healthy controls.

Cortical (grey matter) pathology was visible in 10 patients (6 cortical lesions and 37 leucocortical lesions). Within the 7-T acquisitions, each lesion detected at T2-weighted sequences and/or double inversion recovery sequences was also clearly delineated on corresponding MPRAGE sequences in side-by-side analysis. However, at 1.5 T, the MPRAGE images depicted only 452 of 561 lesions visualized in T2-weighted sequences and/or double inversion recovery sequences. In contrast, when analyzing each sequence separately, we found that the 7-T MPRAGE depicted more lesions than the 7-T FLASH (728 lesions vs 584 lesions), and almost twice as many as the 1.5-T MPRAGE (399 lesions). The 7-T MPRAGE also improved the detection of cortical and leukocortical lesions (15 lesions vs 58 lesions).

CONCLUSIONS: At ultrahigh-field strength, T1-weighted MPRAGE is highly sensitive in detecting MS plaques within the white and the gray brain parenchyma. Our results indicate structural damage beyond demyelination in every lesion depicted, which is in accordance with postmortem histopathological studies. The 7-T MPRAGE clearly delineated every cortical lesion that was visualized by any other MRI sequence at 1.5 or 7 T.

If you look through a microscope you will see more than using a magnifying glass and so it is not surprising that with a 7 tesla machine you see more than with the standard 1.5 telsa or the more high-powered 3 telsa machines. However if you look through a microscope you still often see more than can be see using MRI, the advantage of the latter is that is an imaging tool for the living. With this high powered imaaging it will show us that the disease is even more active than previously shown as it will detect more lesions comming and going

"This study shows that cognitive rehabilitation in MS'ers with cognitive dysfunction may work by recruiting new areas of the brain. This implies that you can train your brain to cope with damage and to compensate for the damage. In other words these results underpin the concept of brain training; we know this works for motor tasks (e.g. walking, skipping, skiing, etc.) why shouldn't it work for cognitive tasks? The problem is that MS is a progressive disease so ongoing damage may undermine the adaptive responses with time. More reason to do this in combination with a DMT that suppresses ongoing damage."

Purpose: To evaluate brain changes after cognitive rehabilitation in MS'ers with clinically stable relapsing-remitting MS (RRMS) by using neuropsychologic assessment and structural and functional MRI techniques.

Structural MRI: delineates the anatomy of the brain, for example lesions and atrophy or shrinkage of the brain.

Functional MRI: delineates function of the brain; how much oxygen and blood a part of the brain requires when doing a particular task.

Materials and Methods: 20 with RR MS and cognitive deficits at baseline were randomly assigned to undergo treatment (n = 10), which entailed computer-assisted cognitive rehabilitation of attention and information processing and executive functions, or to serve as a control subjects (n = 10) without cognitive rehabilitation. All patients underwent a standardized neuropsychologic assessment and MR imaging at baseline and after 12 weeks. Changes in gray matter (GM) volumes on 3D images and changes in normal-appearing white matter (NAWM) architecture on were assessed. Changes in functional activity at functional MR imaging during the Stroop task and at rest were also investigated.

Results: As compared with their performance at baseline, the MS'ers in the treatment group improved at tests of attention and information processing and executive functions. Neither structural modifications to GM volume nor modifications to NAWM architecture were detected at follow-up in both groups. Functional MR imaging demonstrated modifications of the activity of several areas of the brain* at rest in the treatment group compared with the control group. In the treatment group, functional MR imaging changes were correlated with cognitive improvement (P < .0001 to .01).

* For those of you who want to know these areas included the posterior cingulate cortex/precuneus and dorsolateral prefrontal cortex during the Stroop task, as well as modifications of the activity of the anterior cingulum, posterior cingulate cortex and/or precuneus, left dorsolateral prefrontal cortex and right inferior parietal lobule.

Conclusion: Rehabilitation of attention and information processing and executive functions in RR MS may be effected through enhanced recruitment of brain networks subserving the trained functions.

Methods: Relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-beta (IFNB) or glatiramer acetate (GA) were divided into (i) patients without change in DMD, (ii) patients with a change in DMD because of a poor response, and (iii) those with a change in DMD without relation with response. Annualized relapse rate (ARR) and relapse-free proportions were analyzed.

Results: We identified 923 patients with RRMS. Of the 180 who experienced a change because of suboptimal response, 90 switched to another first-line DMT, 38 to mitoxantrone, and 52 to natalizumab. Median ARR in the pre-DMD period on first DMD and second DMD was the following: 1, 1, and 0 for switchers from IFNB to another IFNB (P = 0.0001); 0.67, 1, and 0 for switchers from GA to IFNB (P = 0.01); 1, 1, and 0 for switchers from an IFNB to GA (P = 0.02); 1.1, 1.5, 0.2 for switchers from IFNB or GA to mitoxantrone (P = 0.0001); 0.9, 1, 0 for switchers from IFNB or GA to natalizumab (P = 0.0001).

Conclusions: In patients with RRMS who have a poor response, switch to another DMD may reduce the clinical activity of the disease.

"This study shows that when first line DMDs (IFN-beta and GA) do not have optimal response it is worth switching to another treatment. As expected, a switch from first line DMD to natalizumab or mitoxantrone was beneficial. But it was interesting that even a switch from one IFN to another IFN, higher and even lower dose, can reduce the relapse rate. It is important to note what treatment failure/ disease breakthrough/ sub-optimal response is considered: a single mild relapse in the first months of treatment does not qualify."

Sunday, 26 February 2012

I have been collecting CCSVI papers up to post every now and again post, rather than posting them as they appear. As every, we report without comments. Digest as you will, our take will change if evidence dictates that we change our view. It is interesting that the UK MS Society has got fed up dealing with a monoculture of facebook posts on this subject to the detriment of everything else....More next month......maybe

BACKGROUND: The possible role of the venous system in the pathogenesis of chronic neurodegenerative diseases has been hypothesized for decades. Quite recently, the description of a venous condition defined as chronic cerebrospinal venous insufficiency (CCSVI) and its strong association with multiple sclerosis (MS) has brought back the attention of the scientific community to the hypothesis of an aetiological or concomitant role of an altered venous function in the occurrence of this pathology. CCSVI is identified by sonographic criteria, thus the indication for its possible treatment is based on ultrasound findings.

METHOD: We retrospectively examined 167 consecutive patients affected by clinically defined MS and CCSVI, identified by ultrasound assessment by the presence of at least two sonographic criteria. Ultrasonographic diagnosis of CCSVI was then integrated by venography and intravascular ultrasound examination (in 43 patients). Patients were all submitted to endovascular procedure (venoplasty).

RESULTS: In 37% of cases there was no correspondence between the preoperative ultrasound assessment and the venographic findings. In the event of incongruity between venography and sonography, the intravascular ultrasound examination investigation, when performed, confirmed ultrasound findings in 42% of cases and venography results in 58%. At one month in 12% of cases ultrasound assessment showed the persistence of altered flux. In 67% of cases patients reported subjective amelioration, regarding non-specific symptoms.

CONCLUSION: The pathophysiology of CCSVI is yet to be defined. The superior cava venous system is highly complex in terms of anatomy and possible anomalies, as well as its haemodynamic mechanisms. Further studies are required to define the parameters of diagnosis and treatment of CCSVI.

The methodology to detect CCSVI is inconsistent and venoplasty does not always alter this, but about 70% of people felt better after treatment. However if the methodology is not robust then it is not worth further studies, pants on pants is still pants.

BACKGROUND: We report the outcome of 67 patients after endovascular treatment of chronic cerebro-spinal venous insufficiency in patients with multiple sclerosis.

MATERIALS & METHODS: For evaluating outcome, patients were divided into three groups with respective outcome after three, six and twelve months. Assessment of outcome was done by a disease-specific quality-of-life score that reflects the physical health (physical health composite) and mental health (mental health composite) by a score.

RESULTS: Improvement in physical health composite was significant (P < 0.05) in the three- and six-month groups. Improvement in mental health composite was only significant (P < 0.05) in the three-month group.

CONCLUSION: In conclusion, we can state that the result of endovascular treatment seems to decay although the baseline is still higher than preoperative. To confirm this finding, this study needs to be reproduced in a larger patient population.

In this study there was apparent percieved benefit for just a few months and this was gone within six months to a year. Maybe this is a short-term plcebo effect? As ever do a larger study, but should be do it properly in the first place get and answer and move on.

Purpose: To study the blood flow through the internal jugular veins (IJVs) of the MS population.

Materials and Methods: Two hundred MS patients and 14 normal volunteers were evaluated with magnetic resonance imaging (MRI) at 3T. Contrast-enhanced time-resolved 3D MR angiography and 2D time-of-flight imaging were performed to assess abnormalities in the extracranial vascular anatomy.

Based on this assessment, the MS population was divided into subgroups of non-stenotic (NST), cervical 1 stenotic (blockage) only (C1ST) and cervical 6 stenotic (C6ST) subjects. In this study, 2D phase contrast MR imaging was used to quantify blood flow through major veins and arteries in the neck and flow differences among the groups were analyzed.

Results: Of the 200 MS patients, 87 (43.5%) belonged to the NST group, 50 (25%) belonged to the C1ST group and 63 (31.5%) belonged to the C6ST group.

The total IJV flow normalized to the total arterial flow of the NST group was 75.12 ± 12.22 %. This was significantly higher than that of the C1ST group, 63.93 ± 16.08 % (p<0.0001), which in turn was significantly higher than that of the C6ST group, 52.13 ± 20.71 % (p = 0.001).

Seventy-nine percent of the stenotic groups had a normalized subdominant IJV flow of less than 20%, a combined IJV flow of less than 50% and/or a sub-dominant IJV flow vs. dominant IJV flow ratio of less than 1/3. Only 2% of the NST group had a combined IJV flow of less than 50%, compared to 35% of the stenotic groups.

Conclusion: Blood flow through the IJVs was reduced in the MS population with stenoses compared to those without.

If there is an apparent blockage the blood flow is reduced and no evidence of blockage was found in 45% MSers.

INTRODUCTION: Recent clinical studies have suggested a relationship between multiple sclerosis (MS) and the occurrence of pathological changes in the jugular, vertebral and azygous veins that result in abnormal blood outflow from the brain and the spinal cord. Together, these pathological changes have been designated chronic cerebrospinal venous insufficiency (CCSVI). The aim of the present study was to evaluate the usefulness of duplex Doppler ultrasound in the evaluation of central nervous system venous outflow disturbances in patients suffering from MS.

METHODS: We examined 181 patients with MS, diagnosed on the basis of the McDonald criteria, and 50 healthy volunteer controls. All patients underwent Doppler ultrasound examination of the internal jugular veins (IJV) and vertebral veins (VVs). The presence of outflow disturbances and morphological abnormalities were evaluated.

RESULTS: Pathological changes in the extracranial jugular veins were diagnosed in 148/181 MS patients (82%) and 7/50 control group volunteers (14%). The following abnormalities in the MS group were revealed: the presence of a reflux in the IJVs and/or VVs (54%), narrowing (54%), a complete block in the flow through the IJV (10%) and an abnormal postural control of the cerebral outflow route (25%). These particular pathologies were of statistical significance in the MS group compared with the control group. This study also revealed a correlation between the occurrence of inverted flow in patients in a sitting position and chronic progressive MS (P = 0.0033).

Purpose: To assess cerebral circulation times (CCTs) in patients with multiple sclerosis (MS) and control subjects by using contrast material-enhanced ultrasonography (US) to determine whether vascular abnormalities can be detected in this disease.

Materials and Methods: This study was approved by the local ethics committee, and informed consent was obtained from all subjects. One hundred three patients with MS and 42 control subjects underwent extracranial and transcranial venous echo-color Doppler ultrasonography (US) and contrast-enhanced US. CCT was defined as the difference in arrival time of the US contrast agent bolus between the carotid artery and the internal jugular vein. The presence of chronic cerebrospinal venous insufficiency (CCSVI) was defined according to previously reported criteria for the extracranial and transcranial US techniques. Nonparametric statistics, including the Mann-Whitney U test and the Kruskal-Wallis analysis of variance, were used to compare contrast-enhanced US parameters between groups.

Results: The longest and average CCTs were substantially prolonged in patients with MS compared with those in control subjects (median longest CCT in patients with MS, 6.47 seconds [range, 3.29-29.24 seconds]; that in control subjects, 5.54 seconds [range, 2.57-7.63 seconds]; P < .001; median average CCT in patients with MS, 5.76 seconds [range, 2.64-17.51 seconds]; that in control subjects, 5.01 seconds [range, 2.57-7.06 seconds]; P < .002). No correlation was found between CCTs and clinical parameters.

The prevalence of CCSVI was higher in patients with MS than in control subjects (77% vs 28%, P < .0001). CCT was not significantly different between patients with MS who had CCSVI and patients with MS who did not (P = .182).

Conclusion: These results suggest that contrast-enhanced US with CCT assessment may have a role in the evaluation of cerebral blood flow in patients with MS and that a vascular impairment could be associated with MS. The finding of a prolonged CCT at contrast-enhanced US does not result from outflow impairment.

Background and purpose: MS is associated with increased mortality rates. However, influence of lifestyle parameters remains unknown, and inconsistencies exist regarding findings for causes of death.

Methods: We conducted a population-based cohort study using the General Practice Research Database, Hospital Episode Statistics, and national death certificates (January 2001 through March 2008). To each MS'er (n = 1270), up to six referent subjects without MS were matched by age, gender, and practice. Complex statistical models were used to estimate mortality or death rate ratios (HRs).

Conclusion: British MS'ers have a 3.5-fold increased mortality rate compared with the general population. Smoking and respiratory diseases are major (potentially preventable) factors related to increased mortality rate amongst MS'ers.

"If you have MS and you are a smoker this data is telling you to stop smoking. Don't wait; do it as soon as possible!"

"The excess deaths due to respiratory infections is almost certainly due to swallowing difficulties that come on later in the course of MS and result in aspiration pneumonia."

"The finding that there was not an increase in suicide risk is not what I would have expected. It is well known from other studies that the suicide risk in MS'ers is ~4x higher than the general population and is particularly high in young male MS'ers who are depressed. This is why we take depression in MS so seriously and actively treat it whenever we can."

Mesenchymal stem cells have been demonstrated to ameliorate experimental autoimmune encephalomyelitis (EAE), a model of MS, prompting clinical trials in MS which are currently ongoing. An important question is whether this therapeutic effect generalises to other autoimmune neurological diseases. We performed two trials of efficacy of MSCs in experimental autoimmune neuritis (EAN, an autoimmune demyelinating disease of the peripheral nervous system) in Lewis rats, a model of human autoimmune inflammatory neuropathies. No differences between the groups were found in clinical, histological or electrophysiological outcome measures. This was despite the ability of mesenchymal stem cells to inhibit proliferation of CD4+ T-cells in vitro (outside the body). Therefore the efficacy of MSCs observed in autoimmune CNS demyelination models do not necessarily generalise to the treatment of other forms of neurological autoimmunity.

"Good or bad news? Bad news if you believe MSC's are working via regulating autoimmunity in general. Most treatments that work in EAE also work with EAN. I would be interested to see how EAE in the Lewis rat responds to MSCs in these investigators hands."

"I am not surprised by this result considering how many of the world's population now socialise within Facebook. Our problem is simply time. We already spend a large number of hour per week running the blog and don't have the resource to run a Facebook page as well. Maybe this is an opportunity for us to get some of you involved to help keep the blog, twitter and Facebook pages up-to-date and contemporary."

"Any volunteers? You need to be an MS'ers with lots of spare time, commitment to education and the necessary IT skills."

While motor (power and coordination) and cognitive impairments (memory, calculations, time-keeping, problem solving) are common in MS'ers, research concerning their relationship is limited. These investigators aimed to evaluate associations between cognitive function, walking speed, and falls in MS'ers. They reviewed 81 MS'ers who had had measures of cognitive function, predicted walking speed on the Timed 25-Foot Walk and self-reported fall frequency documented. After controlling for age, gender, and disease severity, slower processing speed and IQ predicted slower walking speed, while poorer verbal memory predicted increased frequency of falls. Poorer verbal memory also predicted increased risk of multiple falls. Thus, specific cognitive functions are related to mobility limitations in MS'ers. These findings suggest that risk assessment for gait decline and falls should include cognitive assessment.

"Whether reduced walking speed and falls are causally related to cognitive impairment will require further study. They may simply be associated with each other due to the severity of MS. The bottom line is that MS is bad disease and that dysfunction in multiple neurological systems occur together. In my experience cognitive impairment is often associated with reduced insight into other disabilities; this makes simple fall prevention strategies that are often based on education and behavioural therapy difficult to implement successfully."

"This is study is that great in that it was retrospective and involved a chart review. In other words it was an audit of pre-existing data. These kinds of studies are best done if the are prospective and pre-planned using a strict and well thought-out protocol. Nevertheless the study highlights the problems of co-disabilities that many MS'ers have to deal with. Preventing disability should be our priority."

Objectives: To report 6-month efficacy and safety outcomes in Japanese patients with relapsing MS treated with fingolimod.

Methods: In this double-blind, parallel-group, phase II study, 171 Japanese MS'ers with relapsing MS were randomized to receive once-daily fingolimod 0.5 mg or 1.25 mg, or matching placebo for six months. The primary and secondary endpoints were the percentages of MS'ers free from gadolinium (Gd)-enhanced lesions at months 3 and 6, and relapses over six months, respectively; safety outcomes were also assessed.

Conclusions: This study demonstrated the clinical efficacy of fingolimod for the first time in Japanese MS'ers, consistent with the established effects of fingolimod in Caucasian patients.

"Nothing surprising with these results; both on the efficacy and adverse effects front. Why repeat a study in Japan? The Japanese regulatory authorities require you to show similar efficacy in a Japanese MS population to get a license to sell your drug in Japan. The big news here is that fingolimod is coming home; it was initially discovered by Japanese scientists back in the early 90's."

Friday, 24 February 2012

Acquired demyelinating syndromes (ADS) can be a first presentation of MS in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Personal and clinical data were collected. 86 patients were identified over 4 years, resulting in an incidence of 0.66/100,000 per year.

"This compares with an adult incidence of MS of ~6-7/100,000 per year."

"Encephalopathy essentially means confusion or delirium; this is very rare in adult-onset disease."

Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001).

"This transmission down the maternal line (mother) is very interesting and is not necessarily due to genetic factors (inheritance of DNA) but could imply epigenetic events due to alterations of how the DNA is controlled (see previous posting on this topic)."

During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/100,000 children/year. A polyfocal disease onset of ADS was most common.

"This study makes you realise how uncommon MS is children and how difficult it can be to make the diagnosis. It is clear that older children have a disease that is similar to adults, compared to smaller children who tend have a different presentation. By studying paediatric MS we should get an idea of the earliest events that cause MS and may be a way of getting to the cause of the disease."

Background: In MS, fatigue is a common and often a disabling symptom. Fatigue has multiple causes with central motor fatigue playing an important role.

Objective: The objective of this study was to analyse the central motor conduction changes (speed and size of the electrical impulse) in relation to muscle contraction force (power) during muscle fatigue and recovery in MS'ers compared to healthy controls.

Methods: A total of 23 MS'ers with fatigue and 13 healthy subjects were assessed during 2 minutes of fatiguing exercise of the abductor digiti minimi muscle of the hand (muscle that makes the little finger move outwards) and the subsequent 7 minutes of recovery. Central motor conduction was quantified by transcranial magnetic stimulation using the triple stimulation protocol and calculating a central conduction index (CCI).

Transcranial magnetic stimulation is a method that uses a magnetic stimulus to activate the nerve cells on the surface of the brain. It is painless.

Results: Force declined to 36% of the pre-exercise level (SD 16%; p < 0.01) in MS'ers and to 44% (SD 9%, p < 0.01) in healthy subjects (group differences, not statistically significant). The decline of the CCI was significantly less marked in patients (-20%, SD 26%, p < 0.05) than in healthy subjects (-57%, SD 15%, p < 0.05; group differences, p < 0.05). The decline of force and CCI were not correlated in either group.

Conclusions: During a fatiguing exercise, the decline in central motor conduction is significantly less pronounced in MS'ers than healthy subjects, although the reduction of force is similar.

"These results are counter-intuitive; I would have expected MS'ers to have declined more than healthy controls. Maybe MS'ers compensate more and therefore have less spare capacity. As with all science the result of this experiment may be incorrect and will need to be reproduced by other groups, preferably using a larger sample size."

Abstract: Cognitive dysfunction frequently occurs during the course of multiple sclerosis (MS). In patients with MS the severity of cognitive manifestations is not closely related to indices of structural brain damage. Neuroplasticity may contribute to the maintenance of normal performance despite scattered brain lesions. Changes in functional organization of the cerebral cortex have been reported by functional magnetic resonance imaging (fMRI) studies in MS. fMRI studies provide an interesting way of understanding how the brain changes its functional organization in response to MS, and might be useful in the study of the effects of rehabilitative or pharmacological therapy on brain plasticity. The purpose of this review is to examine major fMRI studies focusing on cognitive dysfunction in MS.

"It is a pity that our field gets tarnished in this way. Although plagiarism is rare it does occur and there are systems in place to self-regulate the field; hence the retraction and the retraction note. The reputational damage from this event will not be insignificant."

"One form of plagiarism that occurs commonly in medical publishing is self-plagiarism; in that you recycle or reuse your own text. I am guilty of this; for example I have copied-and-pasted text from original research articles I have written into review articles I have been invited to write on the specific topics concerned; rather than generating reams of new text you simply modify the text to make sure it consistent with the style and context of the review. It is important that if you do this you reference the original article. As an editor this is okay. What is not allowed is to try and publish the same data or article, i.e. duplicate publications, without reference to the other article. This is fraudulent and not in keeping with publishing etiquette."

"Some followers of this blog may want to accuse of plagiarism; we copy and paste frequently. The difference is that we always acknowledge the source of the information, by referencing it. The aim of this blog is to interpret research its clinical relevance. To do this we need to present the science and the data, hence the need to copy-and-paste."

Recognizing the need for improved definitions, the National MS Society conducted a survey of physicians who specialized in treating MS. There was a consensus of opinion regarding the definitions of four subtypes of MS. The classification system was published in 1996:

Relapsing-remitting MS (RRMS)

Secondary Progressive MS (SPMS)

Primary Progressive MS (PPMS)

Progressive relapsing MS (PRMS)

"As a result, these are only four subtypes of MS that are currently recognised. Unfortunately, there was no consensus regarding other definitions including chronic progressive, benign and malignant MS. Because the definition of these latter terms is unclear, their use is generally discouraged in scientific publications. This however does not get away from their use in clinical practice, for example the recent posts on fulminant and malignant MS."

Fulminant MS can be accompanied by optic neuritis (ON); however a long interval between ON and the fulminant phase has not been reported. This is a case report of 30-year-old woman with a history of ON that occurred 1 ...

The term fulminant is a carry-over from the pre disease-modifying therapy era. Most cases presenting with Marburg's variant of MS who treated promptly with appropriate therapies, respond to treatment, and can do very well. ...

There have been a few recent queries concerning the clinical course of MS. The first graphical documentation of the various clinical subtypes was in the first edition of "Multiple Sclerosis" by Douglas McAlpine, Nigel Compston and Charles Lumsden.

This text book is now in its 4th edition and is considered by most to be the definitive textbook on multiple sclerosis. The following are some reviewer's comments in relation to the fourth edition:

"The principal merit of this book is the clear and coherent approach of the six authors, who are the world's leading figures in the field, to describing and interpreting the many complex and variable aspects of multiple sclerosis." NEJM

"Since its inception, McAlpine's Multiple Sclerosis has achieved the rare distinction of becoming one of the classical neurological texts of the last century. The possession of this book was a priority for anyone practising neurology and a necessary acquisition for any self-respecting medical library." Brain

"The authors must be warmly congratulated on producing an outstanding reference text that Nigel Compston and his original coauthors would be immensely proud of, their intention at the outset being that of simulating interest in the ever widening field of demyelinating diseases. This book clearly fulfils that legacy and definitively presents the current state of knowledge." J Neurol Neurosurg Psychiatry

"The problem with academic textbooks, particularly in the field of medicine, is that they are usually out of date before the are even published. This is particularly problematic in a rapidly moving field such as neurology. I can't remember when I last used a textbook to find information in relation to a clinical subject; the web is my first port of call."

"I would not recommend MS'ers purchase this textbook; it is not written for MS'ers or lay readers. It assumes the reader has specialist background knowledge in several fields."

Other posts on this blog you may find interesting in relation to the history of MS:

"Some in the field believe that levels >100 nmol/L are normal physiological levels; this is based on blood levels in indigenous populations from Africa with a traditional outdoor lifestyle."

The modified intention to treat analysis included 35 persons in the vitamin D3 group and 33 in the placebo group. Participants were age 21 to 50 years and fully ambulatory (median EDSS 2.5). They studied the effect of supplementing vitamin D3 on the exploratory outcomes annualised relapse rate (ARR), EDSS, multiple sclerosis functional composite (MSFC) components, grip strength, and fatigue.

Conclusion: Supplementation with 20,000 IU vitamin D3 weekly did not result in beneficial effects on the measured MS-related outcomes. This study was not powered to address clinical outcomes, but none of the results were suggestive of an effect in this unselected population of fully ambulatory persons with multiple sclerosis.

Quote: 'This study was not powered to address clinical outcomes.'

"Why then did they report clinical outcomes?"

"Bad science; this study is simply too small to make any claims of a disease-modifying effect. It should report on what it was meant to report on bone mineral density. Reporting this data may be counter-productive and give the impression that vD supplementation has no disease-modifying effects. What we need is properly powered studies!"

Wednesday, 22 February 2012

BACKGROUND: Fatigue is one of the commonest complaints in MS and is frequently reported as the most debilitating by MS'ers. Cognitive fatigue (CF) can be defined as decreased performance with sustained cognitive effort. The effectiveness of the Paced Auditory Serial Addition Task (PASAT) and the Computerized Test of Information Processing (CTIP) at detecting CF was examined in this study. Subjective fatigue was measured using the Fatigue Impact Scale (FIS). The relationship between objective and subjective fatigue was examined.

METHODS: 70 MS and 72 healthy controls (HC) completed the PASAT (3 second and 2 second), CTIP, and FIS as part of a larger battery.

"People find the 2 second PASAT very difficult! Trust me I have tried it myself."

RESULTS: The MS and HCs performed worse on cognitively demanding tasks. Depending on methodology, PASAT performance varied between groups at the 3″ inter-stimulus interval (ISI) and the MS group showed greater susceptibility to CF as their ability to meet task demands declined as the task progressed. CTIP performance for both groups varied differently over time depending on task. The relationship between subjective and objective measures of fatigue varied depending on methodology, with PASAT generally correlating well with the Cognitive Dimension of the FIS.

CONCLUSIONS: The PASAT is a sensitive measure of CF in MS. Additional information is obtained with different scoring methods, with percent dyad scoring method being most sensitive to CF. The ability to detect a relationship between objective and subjective measures varied with methodology.

"I am doubt this work will be reproduced; although I wish it was. I started working on MS fatigue in the late 90's and realised very soon that we don't have a reliable and well-validated outcome measures to measure fatigue. In addition, fatigue is a normal physiological phenomenon and therefore defining what is pathological or excessive fatigue is a hard call. Despite this we need to get on top of fatigue as it is such a big problem for MS'ers. I am also convinced it is a major driver of unemployment and occupational under-achievement in early MS; MS'ers don't necessarily have the cognitive zing to compete on a level playing field with "unaffected" people. Do any of you have any ideas on how to get on top of this problem?"

"In addition, we don't have licensed treatments for MS-related fatigue. A lot of neurologists, including me, use drugs off-license; the commonest being Amantadine and Modafinil. The problem is that the majority of MS'ers find that their fatigue does not respond to these drugs."

"Pharma, we need your help? There are a lot of pharmaceutical targets and potential small molecules to treat fatigue. We need one of you to invest in validating novel fatigue outcome measures and to then invest in some phase 2 exploratory trials."

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